Project Summary/Abstract Malaria is responsible for nearly 500,000 deaths each year with most of those occurring in children under the age of five. There are approximately 200 million new cases each year and over 40% of the world population is at risk for infection. Malaria is caused by parasites in the genus Plasmodium, with P. falciparum being the most common and deadly. To combat emerging resistance, new antimalarial drugs that target novel biological aspects of parasite biology must be developed. Within the parasite is an unusual organelle called the apicoplast. The apicoplast is a relic chloroplast that has lost its photosynthetic capability but retains several important biochemical pathways. The parasite is dependent upon the apicoplast for the biosynthesis of isoprenoid units and it is essential for survival in both the erythrocytic and liver stages of infection, suggesting that it is an excellent drug target. The apicoplast has its own genome along with organelle-specific enzymes for DNA replication and repair. The lone DNA polymerase in the apicoplast (apPOL) is essential and preliminary data suggest it is a highly druggable target. We hypothesize that the inhibition of apPOL will disrupt apicoplast reproduction and cause the delayed death of the Plasmodium parasite. Thus, an apPOL inhibitor could serve as a combinational partner with current fast-acting malaria drugs and for chemoprotection against parasite infection. We propose to employ a target-based approach to identify inhibitors of apPOL that kill the Plasmodium parasite in culture. These inhibitors will then be chemically elaborated and optimized through an x-ray crystal structure-guided medicinal chemistry program. The optimized compounds will be tested in treatment and prophylaxis mouse malaria models. The completion of this proposed research will significantly impact the search for new antimalarial drugs by adding novel compounds to the discovery pipeline.